Magnetic field stimulation techniques

ABSTRACT

The invention involves enhancing brain function by stimulating the brain using magnetic fields. Applications of the new methods include improving the condition of individuals with cognitive disorders, such as depression, and studying the effects of neural stimulation using induced electric fields. These techniques can avoid deleterious effects of psychotropic pharmaceutical treatments, and provide a relatively safe, comfortable, inexpensive means of direct cranial stimulation.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of incorporates by reference U.S.patent application Ser. No. 09/839,258, filed Apr. 20, 2001, which nowis U.S. Pat. No. 6,572,528.

TECHNICAL FIELD

This invention relates to magnetic stimulation techniques, and moreparticularly to neural stimulation using a magnetic field.

BACKGROUND

Repetitive transcranial magnetic stimulation (rTMS) has been used withthe goal of treating depression, see, e.g., George et al., The Journalof Neuropsychiatry and Clinical Neurosciences, 8:373, 1996; Kolbinger etal., Human Psychopharmacology, 10:305, 1995.

One example of an rTMS technique uses a figure-8 surface coil with loopsthat are 4 cm in diameter (Cadwell, Kennewick, Wash.). This coil isplaced next to the scalp, and is usually positioned to direct themagnetic field at the prefrontal cortex of the brain, see, e.g., Georgeet al., The Journal of Neuropsychiatry and Clinical Neurosciences,8:373, 1996. An electric current is run through the magnetic coil togenerate a magnetic field, specifically a sequence of single-cyclesinusoidal pulses where each pulse has a frequency of approximately 1800Hz (or about 560 microseconds per pulse). These pulses are delivered ata repetition rate of 1 to 20 Hz (i.e., one pulse every 0.05 to 1second), see, e.g., George et al, Biological Psychiatry, 48:962, 2000;Eschweiler et al, Psychiatry Research: Neuroimaging Section, 99:161,2000.

Some subjects have declined participation in rTMS studies due to paininduced in the scalp. In addition, seizures have been reported as aresult of rTMS treatment, see, George et al, Biological Psychiatry,48:962, 2000; Wasserman, Electroencephalography and ClinicalNeurophysiology 108:1, 1998.

SUMMARY

The invention concerns enhancing brain function using novel magneticfield techniques. These magnetic field techniques use low fieldstrengths, high repetition rates, and uniform gradients to improve brainfunction.

In one aspect of the present invention, a subject is selected forenhancement of brain function using a magnetic field. The subject's headis then subjected to a time-varying magnetic field having a maximumstrength of less than about 50 G.

Advantages of this aspect of the invention include the following.Subjects with cognitive impairments may benefit from the new treatmentby the lessening of the severity of the condition. Treatment techniquesusing this method can be administered inexpensively with relative safetyand comfort, and offer a substitute for or complement to treatment bymedication. Applications of the new methods include improving thecondition of individuals with cognitive disorders, such as depression,and studying the effects of brain stimulation using induced electricfields.

Embodiments of this aspect of the invention can include one or more ofthe following features. After treating the subject (e.g., a humanpatient), the subject can be evaluated for enhanced brain function. Themagnetic field can have a maximum strength of less than about 10 G. Thefield can also be a gradient magnetic field that is substantiallyuniform (i.e., a magnetic field one or more of whose x, y, or zdirection components varies approximately linearly in space; that is,has a constant gradient to within, e.g., 10%) and unidirectional overthe relevant volume (e.g., the entire brain, or a region of interest ofthe brain such as the prefrontal cortex). The gradient of the magneticfield can be less than about 5 G/cm. The magnetic field can be generatedusing a sequence of trapezoidal pulses of alternating polarity, whereeach pulse has a duration of about 1 millisecond.

In another aspect of the present invention, a subject is selected forenhancement of brain function using a magnetic field. The subject's headis then subjected to a time-varying gradient magnetic field that issubstantially uniform and unidirectional.

In another aspect of the present invention, a subject is selected forenhancement of brain function using a magnetic field. The subject's headis then subjected to a time-varying magnetic field generating by asequence of pulses, each having a duration of less than about 10milliseconds.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice or testing of the present invention, suitable methods andmaterials are described below. All publications, patent applications,patents, and other references mentioned herein are incorporated byreference in their entirety. In case of conflict, the presentspecification, including definitions, will control. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a diagram of a system and apparatus for administering thepresent magnetic field treatments.

FIG. 2 is an example of a magnetic field waveform used in the presentmagnetic field treatment methods.

FIG. 3 is a three-dimensional plot of a magnetic field used in thepresent magnetic field treatment methods.

FIG. 4 is an example of an electric field waveform induced using thepresent magnetic field treatment methods.

FIG. 5 is a contour plot of an electric field used in the presentmagnetic field treatment methods.

FIG. 6 is a three-dimensional plot of an electric field used in thepresent magnetic field treatment methods.

FIG. 7 is a table of the effects of the present treatment on the mood oftwenty-one depressed subjects over forty-three visits, sorted bymedication.

FIG. 8 is an example of a magnetic field waveform used in an example ofrepetitive transcranial magnetic stimulation.

FIG. 9 is a three-dimensional plot of a magnetic field used in anexample of repetitive transcranial magnetic stimulation.

FIG. 10 is an example of an electric field waveform induced using anexample of repetitive transcranial magnetic stimulation.

FIG. 11 is a contour plot of an electric field used in an example ofrepetitive transcranial magnetic stimulation.

FIG. 12 is a three-dimensional plot of an electric field used in anexample of repetitive transcranial magnetic stimulation.

DETAILED DESCRIPTION

Apparatuses and Systems

A device 10 according to the present invention is shown in FIG. 1. Thedevice 10 has a magnetic coil 12, an amplifier 14, and a waveformgenerator 16. The waveform generator 16 (e.g., a general-purposeprogrammable computer or a purpose-built electric circuit) provides anelectrical pulse sequence to the amplifier 14, which amplifies theelectrical signals and provides them to the magnetic coil 12.

The magnetic coil 12 produces a magnetic field in response to electricalsignals received from the amplifier 14. Over the region in which thesubject's brain is positioned, the magnetic field is a gradient magneticfield that is substantially uniform (i.e., the magnetic field strengthvaries substantially linearly in only one direction, e.g., at about 5G/cm, with the variation occurring from anterior to posterior across thesubject's head) and unidirectional (i.e., the vectors representing themagnetic field all point in substantially the same direction, e.g.,along the long axis of the subject's body). (Alternatively, a magneticcoil can be used that generates a substantially uniform andunidirectional gradient magnetic field over only a region of interest ofthe brain, e.g., the left prefrontal cortex.) The magnetic coil 12 islarge enough to accommodate a subject's head, with a diameter of, e.g.,about 35 cm (14 in.).

When being treated with device 10, the subject 18 lays down on astandard patient gurney 20 with a head support 22, with his or her headpositioned inside the coil 12.

Other devices can also be used for administering the present treatmentmethod. For instance, a conventional magnetic resonance imagingapparatus can be used. Alternatively, instead of using a device such asdevice 10 that consists of separate components, the device can insteadintegrate one or more components, e.g., to make the device easilyportable. Alternatively or additionally, the magnetic coil can beincluded in a hat-like structure, and the waveform generator, amplifier,and power source (e.g., a battery) integrated into a control mechanismthat the subject carries or wears, i.e., on his or her subject's belt.The subject can self-administer the treatment, and the treatment can beapplied while the subject is lying down, standing, sitting, or inmotion. Alternatively or additionally, the control device can be pre-setto administer the treatment for specific periods at specific intervalsor continuously.

Methods

Prior to receiving treatment using device 10, a subject is selected as acandidate for enhancement of brain function. This selection is generallyperformed by medical professionals, e.g., because the subject has beendiagnosed as suffering a cognitive impairment. Alternatively, a subjectcould self-select based on a perceived need or desire to enhance brainfunction. Selection can be based on either subjective or objectivecriteria, including, e.g., anxiety, moodiness, depression, lethargy,sleepiness, learning difficulties, and memory impairments.

To administer the treatment, the subject's head is positioned insidecoil 12, and subjected to a time-varying magnetic field. (Alternatively,the subject's entire body could be positioned inside a full-body coil,and subjected to a magnetic field.)

The magnetic pulse train used to generate the time-varying magneticfield is shown in FIG. 2. The pulse train comprises a sequence of pulsesdelivered at a high rate. As discussed in detail below, the magneticfield induces an electrical field in the subject's brain. Thiselectrical field can interact with neurons to cause cognitive effect. Inlight of this, the duration of each individual magnetic pulse isselected to be on the order of the refractory period of an axon, i.e.,on the order of several milliseconds (e.g., 1 to 10 milliseconds), see,e.g., E. R Kandel et al., Principles of Neural Science, 1991, which isincorporated by reference herein. Thus, the pulse duration can be fromon the order of 0.5 milliseconds to 10 milliseconds.

For example, each pulse has a trapezoidal shape, with 128 microsecondramp times (from zero to plateau) and 768 microsecond plateau times (fora total duration of 1.024 milliseconds). The pulses alternate inpolarity, with a short gap between successive pulses. A single pulsetrain comprises 512 successive pulses, and so lasts for about ahalf-second. After a delay of about a second-and-a-half, the pulse trainis repeated (giving one pulse train every two seconds), and thetreatment concludes after about six hundred repetitions (for a totaltreatment time of about 20 minutes). Alternatively, thesecond-and-a-half delay between successive pulse trains can beeliminated.

At the plateau of each trapezoidal pulse, the maximum magnetic fieldstrength is on the order of 5–10 G, with a magnetic field gradient of0.33 G/cm. FIG. 3 shows a three-dimensional plot of the resultantmagnetic field. Pulse sequences yielding maximum magnetic fieldstrengths of up to about 50 G, and maximum magnetic field gradients ofup to about 5 G/cm, can alternatively be used.

These magnetic fields induce electric fields in the subject's brain. Thecharacteristics of these electric fields are defined by the magneticfield parameters according to Maxwell's equation: ∇×E(x, y, z, t)=−∂B(x,y, z, t)/∂t, where ∇×E is the curl of the electric field and

$\frac{\partial B}{\partial t}$is the rate of change of the magnetic field over time. In Cartesiancoordinates, this equation becomes:∂E _(x) /∂y−∂E _(y) /∂x=−∂B _(z) /∂t,∂E _(y) /∂z−∂E _(z) /∂y=−∂B _(x) /∂t,∂E _(z) /∂x−∂E _(x) /∂z=−∂B _(y) /∂t,where the subscripts x, y, and z denote the component of the fieldsalong those respective axes, see, e.g., J. D. Jackson, ClassicalElectrodynamics, 1975, which is incorporated herein by reference.

These equations describe fields in free space (i.e., fields produced inthe absence of other material). When conductive matter, such as braintissue, is placed in the changing magnetic field, a charge distributionis also induced, resulting in an electric field. This electric fieldwill affect the overall electric field in the head. This chargedistribution can alter the free space electric field by up to about 50%,see Roth et al, Electroencephalography and Clinical Neurophysiology,81:47, 1991, which is incorporated herein by reference. The pattern ofthe effect of the charge distribution will depend on the shape andplacement of the subject's head.

Two local field distributions are of particular interest. In the first,the z-component (superior-inferior component) of the magnetic field hasa uniform gradient in the y-direction (anterior-posterior direction),and the y-component has a uniform gradient in the z-direction: (B_(x)=0,B_(y)=G(t)z, B_(z)=G(t)y), where G(t) is the value of the gradient. Inthis case, the electric field is given by:

$\left( {{E_{x} = {{E_{0}(t)} + {\frac{1}{2}{\left( {{\partial{G(t)}}/{\partial t}} \right) \cdot \left( {y^{2} - z^{2}} \right)}}}},{E_{y} = 0},{E_{z} = 0}} \right),$where E₀(t) is a spatially constant field term that depends on the sizeof the coil and, consequently, the extent of the magnetic field. Thepreceding field description applies equally for the two otherorientations, which is obtained by replacement of x with y, y with z,and z with x or by replacement of x with z, y with x and z with y, inboth the vector components and coordinates. In addition, a given vectorcombination of these three field components, which forms an equivalentbut rotated field, is also appropriate. Thus, one approach to applyingthe new treatment techniques involves using a magnetic field that has avector component with a gradient that is substantially uniform, e.g., towithin 10%, in value or direction over a relevant volume of thesubject's brain, e.g., a 8 cm³ volume or the left prefrontal cortex.

In another magnetic field distribution, the magnetic field is uniformover a local volume, which can be expressed as: (B_(x)=0, B_(y)=0,B_(z)=B(t)). The corresponding local electric field is:(E_(x)=E₀(t)−a(∂B(t)/∂t)·y, E_(y)=E₀(t)−(1−a)(∂B(t)/∂t)·y, E_(z)0),where a is an arbitrary parameter determined by the details of coilwinding.

In both situations, if E₀(t) is sufficiently large compared to∂G(t)/∂t·R² or ∂B(t)/∂t·R, where R is an effective radius of the volumeof interest, e.g., the radius of a subject's brain, then the localelectric field is substantially uniform. The preceding field descriptionapplies equally for other orientations and rotations.

FIG. 4 shows the electric field waveform induced in the subject's brainwhen subjected to the magnetic field waveform shown in FIG. 2. Theelectric field waveform is a sequence of alternating monophasic squarepulses of alternating polarity. The width of each induced electric pulsecorresponds to the ramping period for the magnetic field pulses, i.e.,256 microseconds. For the 0.33 G/cm magnetic field pulse amplitude, theelectric field amplitude is approximately 0.7 V/m. This electric fieldstrength is approximately an order of magnitude less than the minimumperipheral nerve stimulation threshold of approximately 6–25 V/m, see,e.g., J. P. Reilly, Medical and Biological Engineering and Computing,27:101, 1989, thus providing an appropriate margin of safety againstcausing pain or seizures in the patient.

FIGS. 5 and 6 are contour and three-dimension plots of this electricfield, respectively. These plots were made by modeling with Biot-Savartstyle integration, see, e.g., J. D. Jackson, Classical Electrodynamics,1975, which is incorporated herein by reference, for free space valuesusing a magnetic field with a vector component having a gradient that issubstantially uniform in value and direction. The plots in FIGS. 5 and 6show that the electric field is substantially uniform in direction andchanges slowly with distance. The direction of the induced electricfield is determined by Maxwell's equations. For a magnetic field thathas a gradient oriented from anterior to posterior across the subject'shead, the induced electric field is oriented in from right to leftacross the subject's head.

EXAMPLES

Experiment

Twenty-one people exhibiting symptoms of depression were selected bymedical professionals and subjected to the present method. Twelvesubjects reported a post-treatment overall mood improvement of at leastone point on the Brief Affect Scale, which involves asking a subject torate his mood after treatment compared to his mood at an earlier time,using a seven point scale: (1) very much improved, (2) much improved,(3) minimally improved, (4) no change, (5) minimally worse, (6) muchworse, (7) very much worse. The results for forty-three visits by thetwenty subjects are given in the table in FIG. 7. As reflected in FIG.7, the effects of the treatment on unmedicated subjects were mostprevalent, with unmedicated subjects demonstrating mood improvementafter seven of nine visits. This demonstrates that the new treatment isuseful both as a substitute for and complement to drug therapy. Theeffects can be substantial; four subjects reported a pronounced,sustained improvement that lasted over a week. There were three reportsby patients of mood worsening.

The treatments were administered using a General Electric 1.5T Sigma MRIscanner. After optional water suppression, slice selective excitation,and a spatial phase encoding pulse, the device applied a train of 512trapezoidal alternating-polarity magnetic field pulses. These pulseswere about one millisecond long, with ramp times of 128 microseconds and768 microsecond plateau times. During the plateau of each pulse, thegradient was 0.33 G/cm, and the maximum magnetic field in the cortex wasabout 5 G. The entire train of 512 pulses was repeated every 2 seconds,six hundred times, for a total treatment time of 20 minutes. FIG. 3 is athree-dimensional plot of this magnetic field, and FIG. 2 is a diagramof the pulse train. The ‘Y’ gradient coil in the magnetic resonancescanner, having an approximate diameter of about 90 cm (36 in.), wasused to apply this sequence, orienting the gradient in theanterior-posterior direction for the supine subjects. The gradient ofthe z-component of the magnetic field from this coil in the y-directionis uniform in both magnitude and direction over a subject's brain towithin about 5%.

The magnetic field induced an electric field in the brains of thesubjects. This electric field was oriented from right to left, from thesubject's perspective, and had a magnitude of approximately 0.7 V/m.FIGS. 5 and 6 respectively show contour and three-dimension plots ofthis electric field modeled for free space values using a wire patternfor a coil similar to the ‘Y’ gradient coil in the Signa MRI system andcomputed with Biot-Savart style integration. The induced electric fieldconsisted of 256 microsecond monophasic square pulses, where each pulsehas a single polarity and an amplitude of approximately 0.72 V/m. Adiagram of this electric field waveform is shown in FIG. 4. To achievethe same electric field with a smaller coil, Maxwell's equations showthat a higher magnetic field is needed. Using a coil with a similarshape but smaller diameter, e.g., a “head-sized” 35 cm (14 in.) coilinstead of a 36-inch “whole-body” gradient coil, to induce a similarsame electric field magnitude would employ a magnetic field that reachesapproximately 50 G in the head. The magnetic field used to induce suchan electric field can have a vector component with a gradient that isslightly less uniform in value and direction, varying by about 10% overthe cranial volume. In addition, a higher magnetic field, e.g., 100 G,can be used with a smaller coil that provides a vector component with asubstantially uniform gradient over only a region, e.g. 8 cm³, of thebrain.

COMPARATIVE EXAMPLE

One example of an rTMS technique uses a figure-8 surface coil with loopsthat are 4 cm in diameter (Cadwell, Kennewick, Wash.). This coil isplaced next to the scalp, and is usually positioned to direct themagnetic field at the prefrontal cortex of the brain, see, e.g., Georgeet al., The Journal of Neuropsychiatry and Clinical Neurosciences,8:373, 1996. An electric current is run through the magnetic coil togenerate a magnetic field, specifically a sequence of single-cyclesinusoidal pulses where each pulse has a frequency of approximately 1800Hz (or about 560 microseconds per pulse). These pulses are delivered ata repetition rate of 1 Hz (i.e., one single-cycle sinusoidal pulse every1 second), see, e.g., George et al, Biological Psychiatry, 48:962, 2000;Eschweiler et al, Psychiatry Research: Neuroimaging Section, 99:161,2000. This waveform is shown in FIG. 8. As the repetition period is muchlonger than the time span on the x-axis, only one single-cyclesinusoidal pulse appears in FIG. 8.

The magnetic field generated by the FIG. 8 waveform is shown in FIG. 9.The field reaches its maximum strength of approximately 10,000 G at theface of the coil. The strength of this magnetic field decreases rapidlyas the distance from the coil increases, to about 0 G at about 6 cm to 8cm, see, e.g., Cohen et al, Electroencephalography and ClinicalNeurophysiology, 75:350, 1990.

FIG. 10 shows the electric field waveform induced in the subject's brainby the magnetic field shown in FIG. 9. This waveform consists of aseries of 560-microsecond single-cycle cosine pulses that repeat every 1Hz.

FIG. 11 shows the contour plot and FIG. 12 shows the three-dimensionalplot of the electric field induced in free space by the magnetic fieldshown in FIG. 2A. The electric field is approximately 120 V/m at theface of the coil, and falls to about 0.02 V/m on the side of the headopposite the coil. The contours of this rapidly diminishing electricfield reflect the shape of the figure-8 surface coil with 4 cm diameterloops, tilted at 45° , and placed 6.7 cm vertically and horizontallyfrom a position equivalent to the center of the head: the electric fieldforms roughly circular loops.

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

1. A method of enhancing brain function, comprising: (a) selecting asubject for enhancement of brain function using a magnetic field; (b)generating a time-varying magnetic field, wherein the magnetic fieldinduces an electric field in air comprising a series of electric pulses,wherein the pulses have a duration less than about 10 milliseconds, andwherein each pulse has a single polarity and the pulses are separated byperiods of substantially no electric field; and (c) subjecting thesubject's head to the time-varying magnetic field.
 2. The method ofclaim 1, further comprising: (d) evaluating the subject for enhancedbrain function after subjecting the subject to the magnetic field. 3.The method of claim 1, wherein the subject is human.
 4. The method ofclaim 1, wherein selecting a subject involves identifying a subjectshowing symptoms of anxiety, depression, or an affective disorder. 5.The method of claim 1, wherein the electric pulses have an amplitudeless than about 5 V/m.
 6. The method of claim 1, wherein the electricfield is substantially unidirectional over at least a region of thebrain.
 7. The method of claim 1, wherein successive electric pulses havealternating polarity.
 8. The method of claim 1, wherein the duration ofeach electric pulse in the series is less than or equal to about 1millisecond.
 9. The method of claim 1, wherein the frequency of theseries of electric pulses is about 1 kHz.
 10. The method of claim 1,wherein the electric field magnitude is substantially spatially uniformover the subject's brain.
 11. The method of claim 1, wherein themagnetic field has a maximum strength of less than about 50 G.
 12. Amethod of enhancing brain function, comprising: (a) selecting a subjectfor enhancement of brain function using a magnetic field; (b) generatinga time-varying magnetic field, wherein the magnetic field induces anelectric field in air comprising a series of electric pulses, whereinthe series of pulses has a frequency of at least about 100 Hz, andwherein each pulse has a single polarity and the pulses are andseparated by periods of substantially no electric field; and (c)subjecting the subject's head to the time-varying magnetic field. 13.The method of claim 12, wherein the subject is human.
 14. The method ofclaim 12, wherein selecting a subject involves identifying a subjectshowing symptoms of anxiety, depression, or an affective disorder. 15.The method of claim 12, wherein the electric pulses have an amplitudeless than about 5 V/m.
 16. The method of claim 12, wherein the electricfield is substantially unidirectional over at least a region of thebrain.
 17. The method of claim 12, wherein successive electric pulseshave alternating polarity.
 18. The method of claim 12, wherein theelectric field magnitude is substantially spatially uniform over thesubject's brain.
 19. The method of claim 12, wherein the series ofpulses have a frequency of about 1 kHz.
 20. The method of claim 12,further comprising: (d) evaluating the subject for enhanced brainfunction after subjecting the subject to the magnetic field.
 21. Amethod of enhancing brain function, comprising: (a) selecting a subjectfor enhancement of brain function using a magnetic field; (b) generatinga time-varying magnetic field, wherein the magnetic field induces anelectric field in air comprising a series of electric pulses, whereinthe electric field is substantially unidirectional over at least aregion of the brain, and wherein each electric pulse has a singlepolarity and the pulses are and separated by periods of substantially noelectric field; and (c) subjecting the subject's head to thetime-varying magnetic field.
 22. The method of claim 21, whereinselecting a subject involves identifying a subject showing symptoms ofanxiety, depression, or an affective disorder.
 23. The method of claim21, wherein the electric pulses have an amplitude less than about 5 V/m.24. The method of claim 21, wherein the region is an interior region ofthe brain.
 25. The method of claim 21, wherein the region is aprefrontal cortex.
 26. The method of claim 21, wherein theunidirectional electric field is oriented from one ear of the subject'shead to the other ear of the subject's head.
 27. The method of claim 21,wherein successive electric pulses have alternating polarity.
 28. Themethod of claim 21, wherein the electric field magnitude issubstantially spatially uniform over the subject's brain.
 29. The methodof claim 21, further comprising: (d) evaluating the subject for enhancedbrain function after subjecting the subject to the magnetic field. 30.The method of claim 21, wherein the subject is human.